Analysis of properties of HIV-1 subtype C envelope glycoprotein

描述（由申请人提供）：HIV-1疾病进展和传播的许多重要生物学决定因素映射到包膜糖蛋白，包括抗体中和敏感性、病毒进入的嗜性和T细胞应答的表位。包膜基因的遗传和表型特征表明，在病毒传播到其他身体隔室和传播中存在瓶颈效应，导致主要同质的病毒群体。然而，在目前的方法，以准确地分配HIV-1辅助受体的使用，区分遗传变异和检测微小变异的艾滋病毒准种内的病人和传播对之间的局限性，导致有争议的结果。此外，研究的患者样本量太小，无法对艾滋病毒传播和发病机制进行广泛的概括。最后，包膜基因的这些不同特性主要在亚型B感染中进行了研究，而在HIV-1亚型C（世界范围内传播最快和最普遍的感染）中的研究则不太清楚。我们假设，一个异质性的HIV-1人口与不同的包膜序列和辅助受体的使用在感染过程中传播，但没有充分的特点和测量我们目前可用的技术。我们建议使用新的和更敏感的方法来确定辅助受体的使用，并进行深入的测序和基因分析的包膜基因从一个大的C亚型临床队列博茨瓦纳。将在纵向样本以及血浆-母乳和母婴对之间研究C亚型感染中的包膜基因。我们计划更深入地研究HIV-1亚型C包膜糖蛋白的特性，具体目标如下：1）确定辅助受体转换的临床和遗传决定因素，2）评估母乳喂养传播HIV-1的相关性，3）使用超深度测序检查通过不同途径的MTCT发生的母婴传播对之间的病毒传播模式。这项研究的结果将进一步了解在传播和疾病进展的背景下病毒的演变，确定传播和疾病进展的临床相关性，并最终深入了解世界上受艾滋病毒影响最严重的地区的预防，治疗和疫苗开发的潜在策略。 公共卫生相关性（由申请人提供）：通过指导艾滋病毒预防和治疗策略的设计，了解艾滋病毒发病机制、传播和临床进展将具有公共卫生相关性。

DESCRIPTION (provided by applicant): Many important biological determinants of HIV-1 disease progression and transmission map to the envelope glycoprotein, including antibody neutralization susceptibility, viral tropism for entry and epitopes for T cell response. Genetic and phenotypic characterizations of the envelope gene suggest a bottleneck effect in the spread of the virus to other body compartments and transmission, resulting in a predominantly homogenous viral population. However, the limitations in current methods to accurately assign HIV-1 coreceptor usage, distinguish genetic variations and detect minor variants in the HIV quasispecies within a patient and between transmission pairs have led to controversial findings. Furthermore, the small patient sample size studied has been too small to make broad generalization regarding mechanisms of HIV transmission and pathogensis. Lastly, these various properties of the envelope gene have been studied predominantly in subtype B infection and less clearly elucidated in HIV-1 subtype C, the most rapidly spreading and prevalent infection worldwide. We hypothesize that a heterogenous HIV-1 population with different envelope sequences and coreceptor usage are transmitted during infection but is not fully characterized and measured by our current available techniques. We propose to use novel and more sensitive methods to determine coreceptor usage and to perform in-depth sequencing and genetic analyses of the envelope gene from a large subtype C clinical cohort from Botswana. The envelope gene in subtype C infection will be studied in longitudinal samples, as well as between plasma-breast milk and mother-infant pairs. We plan to study in greater depth the properties of the HIV-1 subtype C envelope glycoprotein with the following specific aims: 1) identify clinical and genetic determinants of coreceptor switching, 2) assess for correlates of breastfeeding transmission of HIV-1 and 3) examine pattern of viral transmission among mother-to-child transmitting pairs occurring through different routes of MTCT using ultradeep sequencing. The results of this study will further the understanding of viral evolution in the context of transmission and disease progression, identify clinical correlates of transmission and disease progression, and ultimately give insights into potential strategies of prevention, treatment and vaccine development in those parts of the world most affected by HIV. PUBLIC HEALTH RELEVANCE (provided by applicant): Understanding mechanisms of HIV pathogenesis, transmission and clinical progression will have public health relevance by guiding the design of HIV prevention and treatment strategies.